Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway.
Effect of RIF1 on response of non-small-cell lung cancer patients to platinum-based chemotherapy by regulating MYC signaling pathway.
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DOI：
10.7150/ijbs.27710
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发表时间：
2018
影响因子：
9.2
通讯作者：
Zhou HH
中科院分区：
文献类型：
--
作者：
Mei Y;Liu YB;Hu DL;Zhou HH
铂类化疗是晚期非小细胞肺癌（NSCLC）的一线治疗方法。然而，目前还没有有效的指标来预测患者是否会对化疗产生耐药或敏感。此外，对顺铂耐药机制的研究也迫在眉睫。RIF1在DNA复制调控和DNA修复途径中发挥重要作用。然而，RIF1在NSCLC进展和化疗反应中的作用尚不清楚。在本研究中，我们发现RIF1表达与NSCLC患者对铂类化疗的反应相关（n=89， P=0.002）。在接受铂类化疗的患者中，RIF1高表达患者的生存期明显短于低表达患者（P<0.05）。在体外和体内研究中，RIF1敲除增加了NSCLC患者对顺铂的敏感性。此外，RIF1敲低诱导G0/G1期阻滞，增加顺铂诱导的细胞凋亡和DNA损伤。进一步的研究表明，RIF1调节MYC和MYC下游靶点的表达，包括细胞周期和双链断裂（DSB）修复基因，这些基因可能介导了RIF1对顺铂细胞反应的影响。MYC过表达可以逆转RIF1敲低对MYC靶点的抑制作用。综上所述，这些数据表明，RIF1在调节MYC和MYC活化基因中发挥了重要作用，这反过来又有助于细胞对顺铂和NSCLC患者对铂基化疗的反应。RIF1可作为预测非小细胞肺癌患者铂基化疗敏感性及预后的新型生物标志物，指导非小细胞肺癌个体患者调整化疗方案，改善其临床预后。
Platinum-based chemotherapy is used as first-line therapy for advanced non-small-cell lung cancer (NSCLC). However, there is no effective indicator to predict whether the patient would be chemo-resistant or sensitive to the therapy. In addition, it is urgent to elucidate the mechanisms of cisplatin resistance. RIF1 plays important roles in DNA replication regulation and DNA repair pathway. However, the role of RIF1 in NSCLC progression and chemotherapy response is still unknown. In this study, we found that RIF1 expression was correlated with the response of NSCLC patients to platinum-based chemotherapy (n=89, P=0.002). Among patients who have been treated with platinum chemo-therapy, those with high levels of RIF1 expression had significantly shorter survival than those with low RIF1 expression (P<0.05). RIF1 knockdown increased sensitivity to cisplatin in NSCLC patients both in vitro and in vivo. Moreover, RIF1 knockdown induced G0/G1 phase arrest and increased cisplatin-induced apoptosis and DNA damage. Further investigation showed that RIF1 regulated the expression of MYC and MYC downstream targets, including the cell cycle and double-stranded break (DSB) repair genes which might mediate the effect of RIF1 on cellular response to cisplatin. Overexpression of MYC could reverse the inhibition of MYC targets by RIF1 knockdown. Taken together, these data revealed that RIF1 played an important role in regulating MYC and MYC-activated genes, which in turn contributes to cellular response to cisplatin and NSCLC patients' response to platinum-based chemotherapy. RIF1 might serve as a novel biomarker for predicting platinum-based chemo-sensitivity and the prognosis of NSCLC patients, so as to guide the chemotherapy regimen adjustment for individual patient with NSCLC and improve their clinical outcomes.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
3.7
作者：
Mattarocci S;Hafner L;Lezaja A;Shyian M;Shore D
通讯作者：
Shore D
影响因子：
254.7
作者：
Siegel, Rebecca;Ma, Jiemin;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
11.2
作者：
Luoto, Kaisa R.;Meng, Alice X.;Bristow, Robert G.
通讯作者：
Bristow, Robert G.
DOI：
10.1158/1541-7786.mcr-14-0422
发表时间：
2015-04
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Muvarak N;Kelley S;Robert C;Baer MR;Perrotti D;Gambacorti-Passerini C;Civin C;Scheibner K;Rassool FV
通讯作者：
Rassool FV